Summary The goal of this study is to discover novel, mechanism-based pharmacological intervention for Alzheimer?s disease (AD), the most prevalent neurodegenerative disorder. Emerging data suggest that epigenetic mechanisms are central to alterations in gene expression patterns and the ensuing synaptic dysfunctions and behavioral symptoms in AD. Our preliminary studies showed significantly elevated levels of histone modification mark H3K4me3 and its catalyzing enzyme Kmt3e in prefrontal cortex from AD human postmortem tissues and Tau transgenic mouse model of AD. We propose to investigate the hypothesis that Kmt3e inhibitors are able to ameliorate cognitive deficits associated with AD by normalizing gene expression and synaptic functions. To test this, both AD mouse models and AD patient-specific neurons will be used to address two specific aims with combined biochemical, molecular, electrophysiological and behavioral approaches. In Aim 1, we will identify the therapeutic potential of Kmt3e-targeting agents on cognitive and synaptic deficits in AD mouse models. To translate the findings from animal studies to AD patients, in Aim 2, we will generate and compare human neurons derived from AD patients and age-matched control subjects, and examine the capability of Kmt3e inhibitors to reverse synaptic deficits in AD human neurons. Results from this project may lead to new and effective pharmacological agents to treat cognitive and synaptic deficits of AD.